Tuesday, January 17, 2017

Late last month I was contacted via email by a representative for the pharmaceutical company Genentech, asking if I would like to interview one of the researchers who played an instrumental role in the development of the new MS disease modifying drug ocrelizumab. At first I assumed I must’ve received the email as the result of some sort of clerical error, what with my being a mere blogger and all, but I figured if they’re offering, I’m accepting.

Thus, I present the below interview with Dr. Peter Chin, the Group Medical Director of Neuroscience at Genentech. Dr. Chin has been involved with the development of ocrelizumab (tradename Ocrevus) for well over a decade, and was a pioneer in the study of the role of immune system B cells in multiple sclerosis. This line of thinking has upended much of what had previously been thought about the disease, as the working theory up until very recently was that immune system T cells were the primary culprits that should be targeted when developing drugs aimed at alleviating multiple sclerosis. Ocrelizumab is a very close cousin of rituximab, also known by its brand-name Rituxan, another Genentech product which many neuros have been using off label to treat their MS patients.

Ocrevus, an intravenous medication requiring infusions approximately every 6 months, has garnered a tremendous amount of attention of late, as it is the first drug ever to show efficacy in treating progressive MS in a late stage clinical trial and is in the process of being considered for approval for the treatment of PPMS (as well as relapsing multiple sclerosis) by the FDA. The drug has generated blaring headlines and hyperbolic chatter in the medical and mainstream press, and talking directly to Dr. Chin presented a valuable chance to cut through the clutter and get the pertinent info straight from the horse’s mouth. Not to insinuate that Dr. Chin is a horse; au contraire, he proved to be an extremely erudite gentleman during our extensive talk. He was also quite generous with his time, as our scheduled 30 minute interview lasted for nearly an hour.

The following interview is filled with a tremendous amount of important information. It’s been lightly edited for readability. I’ll publish it here without commentary and follow-up next week with my take on the potential promises and pitfalls of ocrelizumab, an intriguing new MS medication.

As you read through the interview, you’ll notice a brand-new feature on these pages called “WK notes”. These are explanations in everyday language of some of the more esoteric medical terminology that cropped up during the interview. And, if anybody’s wondering, “WK” stands for Wheelchair Kamikaze, not Wicked Kool.

WK: Dr. Chin, let me thank you for taking the time to do this interview. To start, could you explain the importance of the relatively recent research into the role of B cells in the Multiple Sclerosis disease process? I understand that when this research first started, it was not in the mainstream of general Multiple Sclerosis research.

Dr. Peter Chin: Genentech started collaborating with leading academic researchers at major universities to look into the possibility that B cells might be important in MS about 15 years ago. To some degree this was not the mainstream line of thinking, but there were researchers who had a scientific hypothesis and believed that B cells might be important because they are the cells that differentiate into cells that secrete antibodies, and antibodies are implicated in the disease pathogenesis (WK note: pathogenesis refers to the conditions that lead to the development of a disease). They are found in lesions and in the cerebral spinal fluid as oligoclonal bands (WK note: more commonly referred to as O-bands, these are one of the primary diagnostic indicators that neurologists look for when examining the spinal fluid of potential MS patients). So there was some rationale, and I think it was an exciting time when the first proof of concept studies unblinded, showing that B cells may play a more important role than anybody thought.

WK: Just to be clear, before this time it was assumed that this was a T cell mediated disease, is that right?

Dr. Chin: That’s correct. The vast majority of efforts in developing new medications up until that point were directed towards T cells.

WK: Genentech was the first to study the use of B cell therapies in MS with the drug Rituxan, whose generic name is rituximab, which was the precursor to ocrelizumab, which will be called Ocrevus if it gets FDA approval, correct?

Dr. Chin: Yes, that’s right. Genentech developed rituximab a long time ago for oncology, and we learned a lot about the medication from there. Rituximab provided a proof of concept that B cells might be important in MS, but we advanced another molecule that we believe has the best potential for long-term treatment from both the safety and efficacy standpoints for people living with MS, and that’s ocrelizumab. Ocrevus is a humanized molecule which is different from rituximab because rituximab is what we call a chimeric antibody, which has a portion of its protein sequence that is derived from mice. (WK note: a chimera is a mythical beast made up of the parts of different animals, such as a winged lion. Chimeric drugs are those that include the DNA of both humans and animals.) Ocrelizumab is a humanized molecule, meaning most of its protein sequence is human. That becomes important, particularly in a chronic disease, because ocrelizumab is hypothetically less likely to generate an immune response against the drug itself than a drug that includes more non-human DNA.

WK: Can you tell us a bit about the proof of concept studies that used rituximab to treat RRMS?

Dr. Chin: Yes, it’s important to recognize that these were small proof of concept studies, with a single dose of rituximab against placebo. It did show a reduction in MRI enhancing lesions, which was the primary endpoint, and also showed about a 50% reduction in relapses against placebo, in a six-month period. So it did provide some preliminary information that targeting CD20 positive B cells might be effective (WK note: CD20 is a protein that appears on the surface of a variety of different types of B cells). Around the same time, ocrelizumab was being studied in rheumatoid arthritis in a dose ranging study. One thing we looked at was multiple doses of ocrelizumab and their effects on B cells as well as efficacy and safety. We also looked at immunogenicity (WK note: immunogenicity is the ability of a substance to provoke a response in the immune system) and found that this was a molecule that had potential for chronic autoimmune conditions, and decided to advance ocrelizumab for Phase II development in RRMS, which led to the Phase III development program which was just published in the New England Journal of Medicine.

WK: PPMS trials were also done with rituximab about 10 years ago, too. Since I am suspected of having PPMS, I was tremendously interested in that particular trial. Can you talk a little bit about that trial?

Dr. Chin: The rituximab PPMS trial is a trial that I was involved in, actually, and it was a Phase II/III study of 439 patients comparing rituximab versus placebo. It was a single study, and it was a negative study. Meaning that the primary endpoint, which was the time to 12 week confirmed disability progression, was not significantly different than placebo.

WK: My understanding is that even though the trial as a whole was negative, when the data was looked at retrospectively there was a subset of patients – primarily those who were younger, less disabled, and had enhancing lesions – that did appear to gain benefit from the drug. Is that correct?

Dr. Chin: That’s right, although this finding was hypothesis generating rather than confirmatory, meaning it was not proven in the study.

WK: Okay, let’s talk about the Ocrevus MS trials, which are creating chatter all around the MS community. Starting with the RRMS studies, some of the results reported were pretty astounding. Could you describe those results?

Dr. Chin: The phase III RMS studies were called OPERA 1 and OPERA 2 (WK note: RMS refers to both RRMS and Relapsing SPMS). These were two, two-year trials – double-blind, double dummy studies – comparing ocrelizumab head-to-head to the interferon beta 1a drug Rebif. Here the relapse reductions were 46% and 47% compared to interferon. There was also a 40% reduction in confirmed disability progression, and approximately 95% reduction in gadolinium enhancing lesions compared to interferon. These are very promising results from an efficacy standpoint, and have the potential to really change the way that MS is treated.

WK: Yes, those are extremely impressive results. Were there any instances of PML, the potentially fatal brain infection that has been seen in patients taking some of the other MS disease modifying drugs, in any of the patients in the Ocrelizumab trials?

Dr. Chin: No cases of PML have been observed in any of the ocrelizumab development trials.

WK: Okay, let’s move onto the PPMS trial, which is really generating tons of buzz. Could you please summarize the studies and their findings?

Dr. Chin: The ORATORIO study is the Phase III double blinded study, lasting more than 2 and half years, comparing ocrelizumab to a true placebo. The primary result of this study indicated a 24% reduction in the risk of 12 week disability progression. Importantly, there was also a 25% reduction in the risk of 24 week disability progression, which is generally considered a more robust outcome measure for disability progression.

That 25% reduction is the reduction in risk over the entire timeframe for all the patients that were included in the trial, and that’s at least 120 weeks, but there were patients who entered the study early in the treatment period that were on the drug for a longer period of time. So the 25% reduction in the risk of disability progression is the figure for the entire cohort for the entire length of the trial.

WK: Okay, so the data from the trial tells us that this new drug for people with primary progressive MS is not reversing disability or stopping the progression of disability, but it is slowing the accrual of disability. Is that a fair assessment?

Dr. Chin: Yes, the primary result of the study is the 24% reduction in 12 week confirmed disability progression. So that is not a measure of improvement, and you’re correct, it shows a delay in the progression of disability as measured by EDSS (WK note: EDSS is a scale that measures the level of disability in MS patients).

WK: Realistically, then, PPMS patients on Ocrevus can expect that they probably will keep progressing, but it would be at a slower rate than if they were left untreated?

Dr. Chin: That’s a hard question to answer for any individual, but the overall results for the population of the study show a slowing of disability production as measured by EDSS, there is a slowing of the worsening of the timed 25 foot walk, which is another major end point in progressive MS trials. This is literally a measure of how long it takes to walk 25 foot feet. There is a slowing in the rate of brain volume loss, and, at least over the course of the trial, there appears to be a stabilization of the accumulation of T2 lesion accumulation. On this end point the placebo treated patients continue to accumulate T2 lesion volume and patients on ocrelizumab experienced a small decrease that was stable over the course of the two and half years or more.

WK: You previously noted that ocrelizumab was tested in trials for the treatment of rheumatoid arthritis. Weren’t those trials halted because of opportunistic infections and patient deaths?

Dr. Chin: There were opportunistic and serious infections observed in the Phase III program in rheumatoid arthritis. What’s important here is that rheumatoid arthritis is a different treatment paradigm. These are patients that are also on concurrent immunosuppressants in addition to ocrelizumab. (WK note: many of the rheumatoid arthritis patients in the ocrelizumab trial were taking other immune suppressing drugs in addition to ocrelizumab.)

WK: And ocrelizumab was also being trialed for treating lupus, and those trials also had to be halted for similar reasons, correct?

Dr. Chin: There were 2 studies in lupus. Ocrelizumab was studied in systemic lupus erythematosus (SLE), and that was discontinued primarily because the expectation for efficacy was low based on another study involving B cell targeting. The other study was on lupus nephritis, and there were serious infections that were observed, but the decision to halt was based on an assessment of potential benefits versus risks.

The same is true for the Rheumatoid Arthritis program. The potential for benefit/risk improvements over existing therapies, based on the data that were already on hand, was deemed not to be promising. So the studies were discontinued.

WK: Were any of these same problems – opportunistic infections and patient deaths – seen in either the RRMS or PPMS Ocrevus trials?

Dr. Chin: The ocrelizumab Phase III safety results for MS overall were very favorable. This is the data that was just published in the New England Journal of Medicine. The proportion of patients in the relapsing study with any adverse event were similar to those who were on beta interferon, and the proportion of patients with any serious adverse event, including serious infections, were also similar to interferons. The same is true with the primary progressive MS trial, which was a slightly longer trial. When compared to placebo the proportion of any adverse event, any serious adverse event, or any serious infection was comparable to placebo.

WK: In looking over the ORATORIO PPMS trial results, it appears that there were higher rates of cancer among the ocrelizumab treated population when compared to the placebo population. I believe the numbers were 2.3% of the ocrelizumab population developed cancers, while .8% of the placebo group developed cancers. Is that of any real concern?

Dr. Chin: There is a numerical imbalance in the number of cases observed, but the overall numbers are small. This is not a confirmed risk, but I will say that patient safety is important to us and we do continue to monitor this in ongoing clinical trials. We don’t believe that the totality of the data supports a causal relationship, but we will continue to monitor this in our ongoing Phase III open label extension studies. So far, in the additional data we’ve accumulated, there is no increase in the rate of cancers being seen.

WK: The earlier rituximab trials demonstrated that there was a subset of the PPMS population on which the drug appeared to be effective – primarily younger patients who were less disabled and had enhancing lesions. In the ocrelizumab PPMS study this group made up about 26% of the test subject population, whereas in the general PPMS population the number of patients displaying those characteristics is thought to be somewhere between 10%-15%. So it would appear that the ocrelizumab study was populated with a higher percentage of patients who might be high responders than are present in the real-life PPMS population. Can you comment on this possible disparity?

Dr. Chin: The first thing I would say is that the study results are designed to assess the efficacy in the entire study population. So this was not a study only of patients of a certain younger age or only of patients who had enhancing lesions or did not have enhancing lesions. I say that because when you look at subgroup results, it’s important to recognize that these studies are not designed to address the efficacy in the subgroups. Also, I would note, that in data that we presented earlier this year that there is a directional consistency, meaning that there is still a reduction in disease worsening in patients who both had enhancing lesions and did not have enhancing lesions at baseline. This was presented at the ACTRIMS meeting in February 2016.

WK: Are there differences between the mechanisms rituximab and ocrelizumab use to eradicate CD20 B cells?

Dr. Chin: There are differences in how they bind to CD20 molecules on the B cells. And there are differences in what we call effector function, and that’s the portion of the antibody that interacts with other elements of the immune system to remove the cells. So, yes, there are differences in the functions of the two molecules.

WK: The mechanism of ocrelizumab in PPMS patients that do have enhancing lesions – which indicate active inflammation within the central nervous system – would presumably be much the same as you would see in the RRMS model, in that the drug clearly reduces inflammation by targeting B cells. Can you propose a mechanism of action for ocrelizumab that would be beneficial for the vast majority patients with PPMS who don’t have signs of enhancing lesions or any other signs of active inflammation in their central nervous systems?

Dr. Chin: That’s a very challenging question, and a good question. I think what you’ve hit on is an area that the entire research community in MS is thinking about. It’s not a question that anyone can answer definitively at this point, because the mechanism of progressive MS and the evolution of progressive MS over time isn’t completely understood. I think there’s a recognition in the research community that the biology has become very complex and how intervening in one way will impact the disease is hard to predict. Genentech is a member of the Industry Forum of the International Progressive MS Alliance, a coalition of organizations that has formed to address the kinds of questions that you’re asking, so we contribute what we can to the understanding of progressive MS. But that’s a really big question that you’re asking.

I think our understanding of B cells currently, which I will acknowledge is ongoing and evolving, is that B cells do interact with T cells, and by removing B cells from circulation we may be breaking that interaction. We also know that B cells differentiate into plasma cells and plasmablasts which create antibodies, which might also be involved. (WK note: plasma cells and plasmablasts are among the more mature types of B cells circulating in the human body.) B cells also create a number of cytokines that also impact and potentially stimulate other parts of the immune system. (WK note: cytokines are chemicals secreted by cells that trigger actions in other cells.) There may be multiple ways that selectively targeting b-cells might be leading to efficacy.

WK: Just a couple of weeks ago we learned that the December 28, 2016 date for and FDA decision on the approval of ocrelizumab had been delayed until March 28, 2017. Can you shed some light on the reasons behind that postponement?

Dr. Chin: We did have an announcement about this extension of the date, and yes it’s March 28, 2017, which is the expected action date by the FDA. The FDA needs more time to review additional data that was submitted during the review, regarding the commercial manufacturing process. What I want to stress is that this is not related to the review of safety or efficacy data. It’s about the manufacturing process and the data regarding that process. This extension of the action date by the FDA is a commonly used procedural tool and they use it to allow more time to evaluate additional information. It’s not uncommon for questions that come up during the review, and as a result of those questions additional data get submitted. It’s just the nature of the process.

WK: As a final question, as a scientist who has devoted a large part of your career to studying MS and progressive MS, what do the trial results from the PPMS ocrelizumab studies indicate to you about the disease, and what can we look forward to in the future for what had previously been an untreatable and rather terrible malady?

Dr. Chin: I think the first thing I’d say is that the data that we just published in the New England Journal are really landmark data for a number of reasons. One, they highlight and confirm that B cells are important in MS, which is still a relatively new concept. That’s a major area of science that Genentech has contributed to that the entire community is continuing to work on. From a clinical trial results standpoint, this is the first molecule that has shown efficacy in both relapsing MS and primary progressive MS. It’s the first molecule under consideration for approval by the FDA for both RRMS and PPMS. It’s an exciting time and an exciting potential new medicine to be working on.

Particularly in regards to primary progressive MS, I want to make the note that Genentech is the only company that has actually done two Phase III studies on primary progressive MS. It’s something that we’ve been very committed to because of the unmet medical needs and the fact that there are no approved therapies. My great hope is that people will start to see that maybe we can do something about primary progressive MS, and build upon this first step with ocrelizumab, which is a very meaningful one.

WK: On behalf of all Wheelchair Kamikaze readers, I’d like to offer a tremendous thank you for doing this interview. On a more personal level, I’d like to thank you for devoting your career to unraveling the mystery of this dreadful disease. It’s tremendously important for a lot of people who suffer from all forms of MS, but especially those who have been without any proven treatment options for so long, who are stuck living with the misery that is progressive MS.

Dr. Chin: Thank you for that, Marc. I think it’s important for you to know that there are hundreds of people at Genentech and Roche who have worked on these primary progressive trials and the RMS trials for many years. I think I can speak for all of them that they do it with a passion for making a difference, understanding the degree of unmet need that’s out there.

I hope readers have found real value in the above interview. I’d love to hear your thoughts in the comments section.

As I stated earlier, I’ll follow this up next week with an essay on my thoughts about all things ocrelizumab, touching on many of the points that I discussed with Dr. Chin. A big thanks goes out to Genentech and Dr. Peter Chin for allowing me the chance to conduct this rather expansive interview.

39 comments:

Marc, It's incredibly nice to see that your great blog has an influence on the medical community, so much so that they are willing to reach out to you and ask you to do an interview on them! I loved this interview and although it is somewhat techy/scientificky, it wasn't too difficult to follow the bouncing ball.

I did find real value in this interview. Even though I only have the cousin to MS(Transverse Myelitis), I keep an eye on the MS community because I know at some point, positive medical research will carry over to us TMers. I've been following you since late 2009 and I reallyu enjoy your updates and everything you have to say. Thank you for doing this. I get tired just thinking about the energy you put into it ;)

Marc, As a person with PPMS, your interview with Dr Chin is quite interesting as it helps me understand the new direction of research into B cells and primary progressive MS. What would we do without your blog? Thanks.

Thank you, Marc, for the most understandable talk on Ocrevus I've been able to find. As a PPMS sufferer, I've been anxiously awaiting its release. I tried Rituxin but had no measurable results, but also no adverse effects. Your addition of the "WK" comments was a godsend! Thank you for your ability to ask the right questions and help us understand where these studies are going.

Hi, thanks for the comment. Regarding Rituxamab versus Ocrelizumab, I'm not sure that people who "failed" on Rituxamab will find any help in Ocrelizumab, since the two compounds really on much the same mechanism of action.

Any port in a storm, though, and I wouldn't blame anybody who chooses to try this new drug, as long as they are well informed.

A really excellent and thorough interview Marc! And the WK explanations were much appreciated. It's very reassuring to think that big pharma is reaching out to patient blog advocates like you to help spread the word on new treatments, but the cynic in me thinks their reaching out, along with the FDA delay (looking into marketing), is to make patients feel hopeful, but is also a way to placate investors. Thanks for posting and I look forward to your take on it soon. All best, Pasopati

Echoing some of the previous comments, I very much appreciate your thoughtful analysis of medical advances in the MS field. As a person who has become extremely disabled from PPMS, I asked my doctor about the appropriateness of Ocrelizumabfor me. She responded that the clinical trial had shown that it might be effective for younger, less disabled people. I believe the above interview concurs.

I filled out a survey a few weeks ago. Although it didn't say who was it was from, I wondered if the source was big Pharma. When it asked what sources I trusted for medical information on MS, I listed your blog. Please continue your excellent work in translating medical research into clear language for the rest of us.

Melinda

PS. Would you consider writing a column on the use of medical marijuana to mitigate the symptoms of MS? My state has legalized this and I am very interested in trying it. Thanks.

I have written about medical marijuana previously, but not extensively.

I would like to see some published studies on medical marijuana for MS. I have seen some on Sativex, which is a cannabis based medicine that is legal in Canada and the UK, and has been specifically approved for spasticity in Multiple Sclerosis.

Marc I am concerned about how the infusion would be given if you have bladder concerns as many M.S. patients do? They usually say to drink lots of water before an infusion & relax! This could be challenging!

I have experienced your very same concerns. Gotta admit, I did not hydrate all that well, in an effort to keep from having to urinate. The Ocrelizumab infusions are long, on the order of five hours, I think. If urinary urgency/frequency is a real problem, I'm sure the infusion center could make some kind of arrangement for you to get your infusion area screened off so that you could use a portable urinal.

At one point, when I was getting regular infusions of IVig, which is another long haul, I talked about getting my infusions while sitting on the toilet in the infusion center. Never came to that, though…

Dearest Mark, THANK YOU for the bestest MS blog ever and, at this time, for this thorough interview with Dr. Chin. You explained very well the Ocrelizumab story.

I am Canadian, 23 years MS, last 3 years SPMS. During the 20 y of RRMS I was on several DMTs, not sure if it helped or not, I progressed to SP, new disabilities creeping in slowly... It now feels strange living without any treatment, other than Botox for 'neurogenic' bladder and medidical marijuana (CBD oil)for muscle spasticity.

My doctor recently mentioned Ocrevus coming soon, but I will not take it...because I am 53 (old), there is not long term use data, and the potential benefits (not really sure what they are) do not outweigh the risk, in my opinion, for me. And I have many more questions, too lazy to ask because I am sure it would be futile ( the answers would be unfavourable for me).

I really hope a treatment would be found soon for PMS. And looking forward to your next post...

I am so happy you were able to speak with Peter and the others working on this drug - I have had several conversations via phone and in person, and run several articles on the progress of their work on ocreluzimab. When you talk with him, you know he has the same sense of disappointment as the rest of us for this delay. There is an earnestness about him that you don't necessarily hear from other researchers. Here's hoping the FDA gets this moving soon! as always, Laura

Hey Laura, thanks for the comment. I'm wondering whether the FDA will fact approved Ocrelizumab for the general PPMS population, or if they will limit it to those with enhancing lesions. As Dr. Chin noted, the study was not set up to identify subgroups of efficacy, which, while good for the pharmaceutical company, might not actually be in the best interest of patients.

There's also that cancer risk, which is very similar to Cladribine, which was rejected because of safety concerns.

I've no doubt the drug will be approved for RRMS, and probably will before the general PPMS population also, if only for lack of other treatments.

I agree wholeheartedly with your assessment of Dr. Chen, he certainly is an earnest and forthright individual.

"here is a numerical imbalance in the number of cases observed, but the overall numbers are small. This is not a confirmed risk, but I will say that patient safety is important to us and we do continue to monitor this in ongoing clinical trials. We don’t believe that the totality of the data supports a causal relationship, but we will continue to monitor this in our ongoing Phase III open label extension studies. So far, in the additional data we’ve accumulated, there is no increase in the rate of cancers being seen."Cancers can take a while to grow (5- 10 years)... if an association (not necessarily causal relationships) is slightly raising red flags now, what can we expect in 10 years time, after continued ongoing use of ocrelizumab?

Certainly, a very reasonable concern. For that matter, what are the long-term ramifications of profound immune suppression? One would think there might be some price to pay for having no B cells for years and years and years at a time. Or T cells, for that matter, which are targeted by many other MS drugs.

Relatively short length of drug trials, while understandable, does not allow for a full comprehension of long-term risks… However, most MS patients who have experienced the ravages of the disease would take almost any form of relief now even at the risk of future complications…

Marc, thank you and congratulations on the interview. You successfully walked the fine line between being a tough and a respectful interviewer. My guess is that Dr. Chin came away impressed with your line of questioning. I look forward to your commentary next week. As for me, I'll probably give this a try even though I realize it's a long shot. I'm older, more disabled, and don't appear to have enhancing lesions. But I'm also desperate, and there are not a lot of choices for PPMS. Thanks again!

Marc, interesting. I was just part of a ppms panel genetech put on. 23% rate compared to copaxone at 30%. They were not to forthcoming, as your interview was. There were 13 ppms patients. Those that had stopped their DMT were in more assisted wheelchair devices. It was a great conference, with genetech and Roche from Switzerland, parent company there. learned a lot, as did genetech. Nobody from a trial there to say side effects, or quality of living of taking drug. Not a cure all, just same rituxin, renamed for better profits? See a couple more in pipeline, affinis oldendous plant from Africa, biotin, vitamin D, and a gut microbe that looks more promissing

Thanks Marc! You have become my go to resource for information on the latest MS related therapies with your ability to break things down in way we can all easily understand. You continue to be such an amazing and invaluable asset for the MS community.

Thank you Mark and Dr Chin!!! I am 40 years old with PPMS. I have no new enhancing lesions. I am in unbearable pain. I am still walking, but stiff everywhere. I am assuming a lot of my pain is from the massive lesion on my brain steam. I have been looking forward to trying this new med for a year now. Thank you for this awesome, and informative interview! BTW I have been struggling to find a knowledgeable pain management doctor. I am only on muscle relaxers and Cymbalta and medical marijuana. I have no quality of life right now, suffering terribly. I am from Bergen County NJ and willing to travel for a knowledgeable and understanding doctor. Any input would be greatly appreciated. Thank you, Sheri

Hi, sorry to hear that you are in so much pain. I very well know how debilitating and soul crushing chronic pain can be. I see a very good pain doctor here in NYC, and since you said you're willing to travel, I would highly recommend her. Here's her contact info:

Andrew, thanks for your comment. You make some valid points, however, your comment does contain several inaccuracies.

The Ocrelizumab Lupus and RA studies were halted because of serious infections and patient deaths, however, none of those infections were PML. I believe most of them had to do with herpes infections.

Also, the Rituxamab RA trials were not halted, and in fact, Rituxamab has been approved for use in treating rheumatoid arthritis since 2006. A retrospective study has found the risk of PML and Rituxamab treated rheumatoid arthritis patients to be approximately one in 25,000.

Certainly, there are safety concerns regarding Ocrelizumab. It is odd that there were no serious infections reported in the RRMS or PPMS trials. Rheumatoid arthritis patients in the Ocrelizumab trials were generally also on concurrent immunosuppressants, though. Not sure about the lupus patients.

The cancer rates are a concern, however, not sure if those will be enough to stop the FDA from approving. Certainly something that needs to be monitored as we move forward.

In the context of the use in MS, Rituxamab has been used off label extensively both here in the states and also in Sweden. A recent retrospective study out of Sweden found that the drug was well tolerated, very effective, and quite safe. Of course, this was a limited population, and we don't know what long-term safety measures (say, 10-15 years) would look like.

On the whole, although Rituxan has been associated with some PML cases over its 20 year period of use (first approved in 1997 for B-cell lymphoma), the PML rates are actually quite low. Especially when compared to a drug like Tysabri, where rates can be as high as one in 99 for patients with certain profiles. Keep in mind, also, that drugs like Gilenya and Tecfidera have also been associated with PML, and in all likelihood most immunosuppressant drugs will heighten the risk of the infection. When assessing risk/benefit, it's up to each patient to decide their tolerance. MS is not a benign disease, and I know quite a few Tysabri patients who refuse to come off of the drug even though they are JC virus positive and are at a higher risk of PML infection, simply because the drug has been so effective for them. Not saying this is the right choice, but, to each his own…

Also, it's important to note that although both Ocrelizumab and Rituxamab Kill B cells, they do so in slightly different biological manners. These differences could cause synergistic differences in the way other immune cells react to the drugs, causing differences in safety and efficacy.

My gut feeling is that Rituxamab is probably a safer drug than Ocrelizumab, and both drugs are likely to be just about as efficacious. Common sense would seem to indicate that Ocrelizumab, over the long-term, would be better tolerated than Rituxamab simply because it is a humanized antibody, whereas Rituxamab is chimeric. How this plays out in the long term as yet to be seen.

I'll go into this in more depth in my next essay, which I hope to have out by the end of this week/early next week.

But regardless if patients in the RA and Lupus ocrelizumab trials died of other opportunistic infections than PML, it is of course still worrying. And of top of this, the high incidents of cancer in the ppms trial with this Ocrelizumab is worrying.

And to be honest, the result of the ppms trial is not impressive, far from it. They loaded the trial with young responders with shorter disease duration than in previous trials. And to reach ca 24 % in reduction of disease progression was, at least for me, a real disappointment.

And to my understanding, the result was yielded mainly due to the fact that it had greatest response among patients with GD lesions. And only about 15% of ppms´s have active GD lesions. So it seems to me, that the ppms trial was not representative of most PPMS patients that neurologists are seeing today.

And as for me, I have no GD lesions at my MRI visits, but still worsening in my ppms. SO how would this Ocrelizumab help me and others without GD lesions. I.e. what is the risk - reward for patients like me (rhetorical question) ?

Correction of facts from my side; You are very correct Mark, it was not PML that caused patients death in lupus and RA. I checked now. It was other form of opportunistic infection that caused the deaths in ocrelizumab patients in the lupus and RA trials. But nonetheless, they all belong to the area of opportunistic infections, including pml.

Thank you for putting out new information on OCREVUS™ (ocrelizumab). When Retuximab was released it actually mentioned a life expectancy for patients, and since you mentioned that you felt Retuximab was safer than OCREVUS™ (ocrelizumab) can I assume that my life expectancy on OCREVUS™ (ocrelizumab) will be reduced even further.I haven't found enough about what kind of cancer the OCREVUS™ (ocrelizumab) may cause, and since I have had MS for over 32 years I am very concerned about the potential "risk verses benefit" of taking either Retuximab or OCREVUS™ (ocrelizumab). Is there anywhere or any article that discusses life expectancy? I am 57 years old, and with having MS most of my life I would still like to at least live as long as I can for my grand children. My biggest fear is becoming a burdon on my family, and even if the chemo does reduce my life expectancy I would hope it increases the quality of my life. I know that there has not been a long enough study on the drug to make an accurate determination, but I know from experience that life expectancy is one element that is determined but for some reason no one wants to discuss. Quality of life has always been my biggest concern since I came down with MS, and I am sure most MS patients want to know the same thing I do which is if I take this chemo how long can I expect to live? I personally would rather be able to stay as mobile as I can before I die, and to me it would make things easier if that portion that every researcher has to include in their study be released to those of us that have to take the drugs. Quality over quantity has always been very important to me.

I haven't come across anything regarding ocrelizumab inducing remyelination. I suppose if a patient was taking it early enough in their disease process, the drug would inhibit inflammation, which would then allow the body to naturally remyelinate. But I don't think the drug has any remyelination properties of its own.

I really appreciated the last sentence in your first paragraph. Classic! Only you could've done such a stellar job with an interview of this magnitude. Accolades to you and Dr. Chin for your willingness & professionalism.

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Regretfully, due to the high volume of e-mail received and the realities of living with progressive MS, I'll no longer be able to respond to all e-mails sent. I do read each note, and will do my best to answer as many messages as I can.

About Me

I'm Marc, a 53-year-old male, living in New York City with my lovely and wonderful wife Karen. Diagnosed with Primary Progressive Multiple Sclerosis in March of 2003, I now require a wheelchair to get around the city. I like to drive the wheelchair at full speed, thus the moniker "Wheelchair Kamikaze". I've managed to rig a camera to my chair, so I'm able to take videos and still photos from the unique vantage point of a wheelchair, which I intend to post here.
Before getting sick, I was the Director of DVD Production for one of the major international music companies. Yes, I was once a member of the Evil Empire...
Prior to my enlistment in the Evil Empire, I worked as a video producer and editor.
I grew up in New York City, and spent the 1980s in Boston (college and postcollege rock 'n roll craziness). During the 1990s, I lived in South Florida, until I woke up one morning and realized I was living in South Florida, came to my senses, and moved back to New York.
I hope you like my blog...